Homologous recombination repair (HRR) eliminates deleterious chromosome lesions and is therefore critical for the maintenance of genome stability. In humans, defects in HRR lead to the tumor phenotype. Studies conducted during the last funding cycle have led to major advances in understanding HRR proteins and mechanisms. Capitalizing on this past success, a combinatorial approach encompassing structural, biochemical, and biological studies will be employed to delineate the integrated roles that several tumor suppressor proteins play in the HRR pathway. The results from this project will allow us to formulate detailed models of HRR mechanisms in human cells. Given the importance of HRR in tumor suppression and in the removal of DNA crosslinks induced by chemotherapeutic agents, our studies have direct relevance to cancer biology and to the development of molecules to evaluate the potential of HRR pathway-targeted therapeutic strategies. As in the past, we will rely on the EMB-ML and SCB cores for their expertise and services. Importantly, our studies will create significant synergy with Projects 2, 3, 5 and 6 and draw links to the entire program, and will thus enhance the impact and significance of our research findings. We anticipate our investigations to help drive the search for connections among HRR and other DNA repair pathways and thereby enable the SBDR program to remain at the frontier of understanding the integrated cellular response to damaged DNA.